RESUMO
During persistent infection of scid mice with Borrelia turicatae, an agent of relapsing fever and neuroborreliosis, there was variation in the surface proteins the bacteria expressed and in disease manifestations over time. Two serotypes, A and B, were isolated from the mice, cloned by limiting dilution, and further characterized. The only discernible difference between the two variants was in the size of the major surface protein they expressed: serotype A had a variable major protein (Vmp) of 23,000, and serotype B had a Vmp of 20,000. When other scid mice were inoculated with clonal populations of A and B, the infections were similar with respect to onset and degree of spirochetemia, involvement of the eye and heart, and occurrence of a peripheral vestibular disorder. However, there were differences between the serotypes in other respects: (a) serotype B but not A caused reddened and significantly enlarged joints, markedly impaired performance on a walking bar, and severe arthritis by histologic examination; (b) serotype A but not B invaded the central nervous system during early infection; and (c) serotype A penetrated monolayers of human umbilical vein endothelial cells more readily than did serotype B. The combination of arthritis, myocarditis, and neurologic disease resembled human Lyme borreliosis. The findings indicate that differences in disease expression are determined by variable surface proteins of the bacterium and that scid mouse infections with B. turicatae provide a model for the study of the pathogenesis of Lyme borreliosis and other persistent spirochetal diseases.
Assuntos
Proteínas da Membrana Bacteriana Externa/biossíntese , Grupo Borrelia Burgdorferi/metabolismo , Doença de Lyme/microbiologia , Animais , Artrite Infecciosa/microbiologia , Artrite Infecciosa/patologia , Proteínas da Membrana Bacteriana Externa/imunologia , Grupo Borrelia Burgdorferi/classificação , Grupo Borrelia Burgdorferi/imunologia , Encéfalo/microbiologia , Feminino , Humanos , Doença de Lyme/imunologia , Doença de Lyme/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Sorotipagem , Especificidade da EspécieRESUMO
BACKGROUND: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. METHODS: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon beta-1b (IFNbeta1b) in the BECOME study. FINDINGS: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for >or=1 year, 103 (18.8%) were still visible >or=12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up >or=1 year converted to CBH, 9.8% with IFNbeta1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNbeta1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. INTERPRETATION: Only a minority of new brain lesions in patients with MS treated with GA or IFNbeta1b convert to CBH.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Encéfalo/patologia , Imunossupressores/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Peptídeos/uso terapêutico , Encéfalo/efeitos dos fármacos , Acetato de Glatiramer , Humanos , Interferon beta-1b , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Fatores de TempoRESUMO
Cladribine (2-chlorodeoxyadenosine) is an immunosuppressant drug previously evaluated in multiple sclerosis (MS) with variable results. We report six patients with aggressive relapsing MS who despite a poor response to other therapies had a favourable clinical evolution after cladribine. Four women and two men with a rapid increase in the number and severity of relapses leading to increasing disability [mean Expanded Disability Status Scale (EDSS) 6.42, standard deviation +/- 0.58, mean relapse rate per year in the 2 years prior to study entry 2.67 +/- 0.75] were retrospectively evaluated. Brain magnetic resonance imaging (MRI) performed in five patients showed active disease with gadolinium-enhancing lesions. Cladribine was given at 0.07 mg/kg/day for five consecutive days once monthly with a total of 2- to 4-monthly courses. After 6 months, mean EDSS decreased to 3.75 +/- 1.64 and MRIs showed a decrease or suppression in the number of gadolinium-enhancing lesions. After 1 year from first dose, cladribine dosage was repeated in four patients because of recurrence of relapses with subsequent similar positive clinical results. In the follow-up period (49.33 +/- 39.66 months), the mean relapse rate decreased to 0.71 +/- 0.55 and no unexpected or serious adverse events were observed.
Assuntos
Cladribina/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adolescente , Adulto , Avaliação da Deficiência , Feminino , Seguimentos , Humanos , Masculino , Estudos RetrospectivosRESUMO
Cerebral amyloid angiopathy (CAA) is conspicuous for its association with Alzheimer disease (AD) and as a cause of lobar hemorrhages in the elderly, but its role in cerebral infarction is less clear. There is evidence that CAA may also be a risk factor for ischemic infarction in AD. To further investigate CAA as a risk factor for infarction, we studied 108 cases of recent cerebral or cerebellar infarction diagnosed in tissue samples obtained from surgical material. There were 69 males and 39 females with a mean age of 52 yr (range 1-86). The majority of biopsies were obtained from the frontal and parietal lobes. Radiological studies demonstrated a lesion confined to a vascular distribution in 12 of the 17 (71%) cases examined. Microscopic sections stained with hematoxylin and eosin revealed complete, organizing infarction in 107 cases with areas of coagulative necrosis, anoxic-ischemic neuronal injury, inflammation, macrophages, vascular proliferation, gliosis, and swollen axons. One case showed an incomplete infarct. Most cases also exhibited a minor hemorrhagic component with hemosiderin and hematoidin pigments. CAA, defined as amyloid deposition in the walls of leptomeningeal and parenchymal arteries, was found by immunohistochemical stains for beta amyloid in 14 (13%) cases of complete cerebral infarct. Cortical beta amyloid plaques were found by immunohistochemistry in 19 (17%) cases. Cerebral or cerebellar tissues containing cortex and leptomeninges obtained from 136 patients with a mean age of 52 yr (range 1-85) during surgical procedures for diagnosis of primary or metastatic neoplasms and demyelinating lesions were used as age-matched controls. In this control group, CAA was found in 5 (3.7%) and beta amyloid plaques in 19 (14%). The results indicate that CAA, but not beta amyloid plaque formation, is significantly more common in patients with ischemic cerebral infarction than in age-matched controls with nonvascular lesions (odds ratio 3.8; 95% confidence interval 1.3-10.9; p < 0.01). Our results indicate that CAA is a risk factor for ischemic cerebral infarction in the population studied.
Assuntos
Encéfalo/patologia , Angiopatia Amiloide Cerebral/patologia , Infarto Cerebral/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Isquemia Encefálica/patologia , Estudos de Casos e Controles , Cerebelo/patologia , Infarto Cerebral/epidemiologia , Criança , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Valores de Referência , Fatores de RiscoRESUMO
A 12-year-old girl who had zoster ophthalmicus 10 months earlier presented with hemiparesis and corresponding basal ganglionic infarction related to middle cerebral artery branch thrombosis ipsilateral to the zoster. Hematologic evaluation disclosed protein C deficiency. This represents the first zoster-associated stroke reported in childhood associated with protein C deficiency, with extension of the latency period between zoster and infarction, previously reported to be 6 months.
Assuntos
Herpes Zoster Oftálmico/complicações , Deficiência de Proteína C/complicações , Acidente Vascular Cerebral/etiologia , Encéfalo/patologia , Criança , Feminino , Herpes Zoster Oftálmico/patologia , Humanos , Imageamento por Ressonância Magnética , Tempo de Reação , Acidente Vascular Cerebral/patologiaRESUMO
The diagnosis of human LNB can be difficult, because its major clinical manifestations--meningitis, facial palsy, radiculitis, and neuritis--are non-specific and the characteristic skin lesion is usually absent at the time of neurological involvement. Thus, CSF assays are often used in diagnosis. Culture of CSF is rarely performed because it has a low yield and requires special culture medium. PCR of the CSF identified spirochetal DNA in clinical specimens with greater sensitivity, but it suffers from a number of disadvantages. Measurement of specific antibody in the CSF also has its limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. The recent development of the nonhumane primate (NHP) model of LNB allows us to address this need in a faithful model of human LNB. We compared PCR and culture in their ability to detect spirochetal presence in the CSF and brain tissue of infected NHPs, and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Using these four assays (PCR, culture, MIT, and CSF Ab) at least one assay for spirochetal presence in CSFs from NHPs was positive in 87% of CSFs tested during early infection in the CNS. Detection of spirochetal presence by PCR, MIT, and culture in the CSF was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR in infected NHPs; antibody in the CSF was the most useful assay in immunocompetent NHPs. This is the first study demonstrating that a bioassay using inoculation of mice, the mouse infectivity test (MIT), has potential as a useful adjunct in the diagnosis of LNB. The MIT for LNB was modeled after the rabbit infectivity test or RIT, which is considered the "gold standard" for the diagnosis of the related CNS infection, neurosyphilis, and felt to be very sensitive and specific. The presence of specific anti-B. burgdorferi antibody in the CSF is the most widely used assay for Lyme neuroborreliosis. In the immunocompetent NHPs in our study it was a very successful assay for detection of CNS invasion. However, it is frequently false-negative, especially early in the course of the infection, or if there is transient immunosuppression. Transient suppression of the anti-B. burgdorferi immune response in the human could occur in instances of co-infection, i.e. simultaneous transmission via the tick of another pathogen other than B. burgdorferi. Thus, mild immunosuppression as accomplished in our NHPs with corticosteroids was designed to mimic conditions in the human host which allow B. burgdorferi in the natural state to gain a firm foothold in the central nervous system in the 10-15% of B. burgdorferi-infected patients who develop clinically symptomatic nervous system disease. This study is the first to compare utility of available diagnostic techniques in LNB in which necropsy proved presence of infection in the CNS. None of the assays was ideal for all conditions, and the utility of the assay was associated with the host immune status. The differences in the responses of immunocompromised and immunocompetent NHPs in this study were striking. In immunocompetent NHPs the window of opportunity for CNS invasion prior to the development of CSF antibody was brief, and the chance of detection of spirochete low by any of the three techniques used (i.e. culture, PCR, or MIT); in this group, measurement of CSF antibody was generally diagnostic. In immunocompromised NHPs, intrathecal antibody production was delayed, and this helpful diagnostic assay was false-negative; diagnosis required more labor-intensive assays such as PCR, culture, an
Assuntos
Grupo Borrelia Burgdorferi/patogenicidade , Doenças do Sistema Nervoso Central/microbiologia , Doença de Lyme/microbiologia , Animais , Modelos Animais de Doenças , Humanos , Doença de Lyme/líquido cefalorraquidiano , Macaca mulattaRESUMO
OBJECTIVE: There is a significant unmet need for serum biomarkers in relapsing-remitting multiple sclerosis (RRMS) that are predictive of therapeutic response to disease-modifying therapies. Following a recent Stanford study which reported that pretreatment levels of serum interleukin (IL)-17F could predict poor response to interferon-ß (IFNß) therapy, we sought to validate the finding using samples from a large clinical trial. METHODS: The validation cohort included 54 good responders (GR) and 64 poor responders (PR) selected from 762 subjects with RRMS from the IM IFNß-1a dose comparison study (Avonex study C94-805). Subjects were classified as GR and PR based on the number of relapses, Expanded Disability Status Scale score, and new and enlarging T2 lesions on MRI. Serum samples were assayed for IL-17F using a multiplexed Luminex assay and for IL-17F/F using an ELISA. Replicate aliquots from the Stanford study were also assayed to assure reproducibility of methods. RESULTS: Median pretreatment and post-treatment serum IL-17F levels were not statistically significantly different between GR and PR, and serum IL-7/IL-17F ratios were also not predictive of response status. Replicate aliquots from the Stanford study showed good correlation to their original cohort (r = 0.77). CONCLUSIONS: We were unable to validate the finding that serum IL-17F is a predictor of PR in a large independent cohort of subjects with RRMS. Differences in patient populations and methodology might explain the failure to validate the results from the Stanford study.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Interferon beta/administração & dosagem , Interleucina-17/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Injeções Intramusculares , Interferon beta-1a , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML. METHODS: Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database. RESULTS: At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores. CONCLUSIONS: Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Adulto , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Causas de Morte , Avaliação da Deficiência , Diagnóstico Precoce , Feminino , Humanos , Avaliação de Estado de Karnofsky , Leucoencefalopatia Multifocal Progressiva/mortalidade , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Natalizumab , Valor Preditivo dos Testes , Vigilância de Produtos Comercializados , Prognóstico , Fatores Socioeconômicos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Mice infected with relapsing fever (RF) spirochaetes survive recurrent waves of high-level bacteraemia with little, if any, clinical complications or tissue injury. In the absence of B-cells, peak bacteraemia does not resolve, resulting in multi-organ complications. During peak bacteraemia, large amounts of interleukin-10 (IL-10) are produced in blood and tissues. In mice unable to clear peak bacteraemia, exogenous IL-10 greatly reduced the clinical manifestations, serum levels of CXCL13, cerebral microgliosis, and the pathogen load. In contrast, IL-10 deficiency in mice unable to clear peak bacteraemia resulted in microvascular complications with distinct severities, depending on the serotype: serotype 2 (Bt2), which causes peak bacteraemia of c. 10(8)/mL, resulted in rapid death from subarachnoid and intraparenchymal haemorrhage; in contrast, serotype 1, which causes peak bacteraemia of c. 10(7)/mL, resulted in milder multi-organ haemorrhage and thrombosis. IL-10 deficiency also resulted in multi-organ haemorrhage and thrombosis with infarction in wild-type mice despite lower peak bacteraemia. Two mechanisms for pathogen control have been identified: antibody clearance of peak bacteraemia, and antibody-independent lowering of bacteraemia via phagocytosis in the spleen. IL-10 plays opposite roles in pathogen control, depending on the severity of bacteraemia: during persistent high bacteraemia, IL-10 helps to control it by protecting innate immune cells from apoptosis; in contrast, during transient peak bacteraemia, IL-10 slows down antibody-mediated clearance. A successful outcome from RF depends on a balanced immune response to clear bacteraemia while avoiding microvascular injury, in which production of IL-10, in response to the pathogen load, plays a critical role.
Assuntos
Febre Recorrente/imunologia , Febre Recorrente/patologia , Animais , Anticorpos Antibacterianos/imunologia , Linfócitos B/imunologia , Bacteriemia/imunologia , Bacteriemia/patologia , Quimiocina CXCL13/sangue , Interleucina-10/imunologia , Camundongos , Microvasos/patologia , Fagocitose/imunologiaRESUMO
No disponible
Assuntos
Humanos , Masculino , Idoso , Degeneração Paraneoplásica Cerebelar/diagnóstico , Leucoencefalopatias/diagnóstico , Células de Purkinje/fisiologia , Líquido CefalorraquidianoRESUMO
BACKGROUND: There are no published MRI studies comparing interferon beta 1b (IFNbeta-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). OBJECTIVE: To compare the efficacy of IFNbeta-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI. METHODS: A total of 75 patients with relapsing-remitting MS or clinically isolated syndromes were randomized to standard doses of IFNbeta-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement. The primary outcome was the number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery (FLAIR) lesions. Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years. RESULTS: Baseline characteristics were similar between the groups. The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1-12, 0.63 (2.76) for IFNbeta-1b, and 0.58 (2.45) for GA (p = 0.58). There were no differences in new lesion or clinical relapses for 2 years. Only 4.4% of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions. CONCLUSION: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Interferon beta/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Peptídeos/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Sistema Nervoso Central/imunologia , Progressão da Doença , Feminino , Acetato de Glatiramer , Humanos , Interferon beta-1b , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Valor Preditivo dos Testes , Prevenção Secundária , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
Cognitive impairment in multiple sclerosis is difficult to study because of the heterogeneity and variability of this disease. The gold standard for measurement of cognitive function in multiple sclerosis is a full battery of neurocognitive tests, which is time consuming and expensive. Some cognitive tests like the PASAT, a measure of working verbal memory and processing speed, have been proposed for screening and follow-up of cognitive function in clinical trials. We studied whether we could measure cognitive function in multiple sclerosis over the Internet. For this we used the Cognitive Stability Index (CSI)trade mark, developed for persons with known or suspected primary central nervous system illness. The CSI was compared with formal neurocognitive testing (NPsych) and the PASAT in a cross-sectional study of 40 consecutive multiple sclerosis patients with subjective cognitive complaints. NPsych revealed that only 18 of the 40 patients (46%) were cognitively impaired. Although both the CSI and the PASAT were equalivalent in their specificity (86%), the CSI was significantly more sensitive than the PASAT (83% versus 28%). We conclude that the CSI, because of its availability over the Internet, has great potential as a tool for screening and follow up of cognitive function in multiple sclerosis.
Assuntos
Cognição , Internet , Esclerose Múltipla/psicologia , Testes Psicológicos , Adulto , Idade de Início , Transtornos Cognitivos/epidemiologia , Escolaridade , Família , Feminino , Lateralidade Funcional , História do Século XVIII , Humanos , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Teste de Sequência Alfanumérica , Escalas de WechslerRESUMO
The natural habitat of Paracoccidioides brasiliensis, the aetiologic agent of paracoccidioidomycosis, has not been determined. Consequently, the events leading to the acquisition of infection remain controversial. To identify factors associated with infection in endemic areas we conducted a survey in three rural communities in Colombia where we had previously diagnosed paracoccidioidomycosis in children. Permanent residents were surveyed taking into consideration environmental and occupational variables. Skin tests were used to classify subjects as infected or non-infected. Variables found associated with infection were: (i) community A: previous residence around Porce river and agriculture in vegetable gardens; (ii) community C: frequent use of specific water sources; (iii) community V: housekeeping activities, and (iv) total group: age > 25 years and contact with bats. Residents in communities with higher prevalence of infection were older, had more complex residence history, and referred more contact with armadillos than residents of communities with lower infection.
Assuntos
Paracoccidioidomicose/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Colômbia/epidemiologia , Meio Ambiente , Feminino , Proteínas Fúngicas/imunologia , Histoplasmina/imunologia , Humanos , Masculino , Ocupações , Paracoccidioidomicose/epidemiologia , Dinâmica Populacional , Análise de Regressão , Saúde da População Rural , Testes CutâneosRESUMO
The spirochetal disease relapsing fever is caused by different Borrelia species. Relapsing fever is well recognized as an infection of the blood, but little is known about its predilection for the nervous system and the eyes. To investigate neurological and ocular involvement during relapsing fever, we reviewed the clinical manifestations, pathology, and treatment of relapsing fever of humans and experimental animals. The results indicate that Borrelia turicatae and Borrelia duttonii, the agents of tick-borne relapsing fever in southwestern North America and sub-Saharan Africa, respectively, cause neurological involvement as often as Borrelia burgdorferi in Lyme disease. Evidence of this is the frequent occurrence of lymphocytic meningitis and peripheral facial palsy in human disease; the identification of spirochetes in the brain and other nervous tissues of humans, animals, and arthropod vectors; and the persistence of brain infection after treatment with antibiotics that do not readily penetrate the blood-brain barrier.
Assuntos
Encefalopatias/etiologia , Febre Recorrente/complicações , Animais , Antibacterianos/uso terapêutico , Encéfalo/patologia , Infecções Oculares Bacterianas/etiologia , Humanos , Lactamas , Metais/uso terapêutico , Febre Recorrente/tratamento farmacológico , Febre Recorrente/patologia , Tetraciclinas/uso terapêuticoRESUMO
Similarity of pathology and disease progression make the non-human primate (NHP) model of Lyme neuroborreliosis appropriate and valuable. In the NHP model of Lyme neuroborreliosis, spirochetal density in the nervous system and other tissues has been measured by polymerase chain reaction and correlated to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid and to inflammation in tissues. Despite the demonstrable presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, only minor inflammation of the central nervous system occurs, though inflammation can be demonstrated in other tissues. Infected animals also develop anti-Borrelia burgdorferi antibody in the serum, although increased amplitude of antibody is not predictive of higher levels of infection. The NHP model continues to provide important insight into the disease process in humans.
Assuntos
Borrelia burgdorferi/imunologia , Modelos Animais de Doenças , Doença de Lyme/microbiologia , Neuroborreliose de Lyme/imunologia , Macaca mulatta , Animais , Formação de Anticorpos , Variação Antigênica , Humanos , Imunidade Celular , Imunização Passiva , Doença de Lyme/imunologia , CamundongosRESUMO
Studies of the interactions of relapsing fever Borrelia species with cultured neural cells have not been reported. In the present work, the interaction of the relapsing fever agents Borrelia hermsii and Borrelia turicatae with cultured neural and endothelial cells was studied and compared with Borrelia burgdorferi, the agent of Lyme disease. All Borrelia species bound each cell type tested. Host cell association was time-dependent and saturable. With the exception of human neuron cells, B. hermsii and B. turicatae associated to a greater degree with neural-derived cell types than did B. burgdorferi. In contrast, B. burgdorferi associated better with endothelial cells than did the relapsing fever borreliae. B. burgdorferi were found in human neuron cells to compete for association sites with B. hermsii and B. turicatae, suggesting the existence of some identity between the ligands or receptors used. Data indicate that the study of in vitro association of Borrelia species with neural-derived cells may provide valuable information for a better understanding of pathogenic mechanisms in neuroborreliosis.
Assuntos
Borrelia/patogenicidade , Neurônios/microbiologia , Grupo Borrelia Burgdorferi/patogenicidade , Células Cultivadas , Endotélio Vascular/microbiologia , Humanos , Técnicas In Vitro , Doenças do Sistema Nervoso/microbiologia , Especificidade da EspécieRESUMO
Serotypes A and B of the relapsing fever spirochete Borrelia turicatae produce different disease manifestations in infected mice. Whereas serotype B causes more severe arthritis and reaches higher densities in the blood of mice than serotype A, serotype A invades the central nervous system earlier than serotype B during infection. These differences between serotypes A and B in mice are associated with the expression of different surface proteins, VspA and VspB, respectively, in the culture medium. To determine whether these proteins, in particular, VspB, are also expressed in vivo, scid mice infected with B. turicatae were studied. The expression of VspB by spirochetes in the blood was demonstrated in Coomassie blue-stained polyacrylamide gels and Western blots with a specific monoclonal antibody. Indirect immunofluorescence and immunoperoxidase studies confirmed the expression of VspB in the blood and also demonstrated VspB expression in the joints and heart. The gene for VspB was next identified and cloned by using partial amino acid sequencing, reverse transcriptase PCR, and a specific monoclonal antibody. The vspB gene encodes a protein of 216 amino acids that is 68% identical to VspA of B. turicatae and 44 to 56% identical to representative Vsp and OspC lipoproteins of other Borrelia spp. The processed VspB protein was distinguished from 26 other Vsp and OspC proteins by a high predicted isoelectric point at 9.39. The promoter region for vspB was similar to the promoter region for the vsp33 gene of Borrelia hermsii and for the ospC gene of Borrelia burgdorferi, two genes known to be environmentally regulated. These studies established that the virulence-associated VspB protein is expressed by spirochetes in the mouse and that VspB is a novel member of the Vsp-OspC family of proteins.
Assuntos
Antígenos de Bactérias , Proteínas da Membrana Bacteriana Externa/biossíntese , Infecções por Borrelia/metabolismo , Borrelia/metabolismo , Sequência de Aminoácidos , Animais , Proteínas da Membrana Bacteriana Externa/sangue , Proteínas da Membrana Bacteriana Externa/genética , Sequência de Bases , Western Blotting , Infecções por Borrelia/sangue , Infecções por Borrelia/patologia , Enzimas de Restrição do DNA , DNA Bacteriano , Eletroforese em Gel de Poliacrilamida , Feminino , Imunofluorescência , Técnicas Imunoenzimáticas , Masculino , Camundongos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Homologia de Sequência do Ácido NucleicoRESUMO
The spirochetal disease relapsing fever is notable not only for multiphasic antigenic variation but also for central neurologic manifestations. To further characterize involvement of the brain in this disorder, immunocompetent and -deficient mice were infected with Borrelia hermsii. Immunodeficient mice were treated while spirochetemic with neutralizing IgM monoclonal antibodies to the infecting serotype. Blood, cerebrospinal fluid, and brain tissue were examined by culture and polymerase chain reaction. In immunocompetent mice, antigenic variation occurred in the brain as well as in the blood. In immunodeficient mice, the infecting serotype was still present in the brain after it had been eliminated from the blood by the administered antibodies. These latter results cannot be accounted for by contamination of brain tissue and cerebrospinal fluid by blood and, hence, establish the direct involvement of the central nervous system in this experimental infection.
Assuntos
Antígenos de Bactérias , Proteínas da Membrana Bacteriana Externa , Borrelia/genética , Encefalopatias/microbiologia , Febre Recorrente/microbiologia , Sequência de Aminoácidos , Animais , Variação Antigênica , Antígenos de Superfície/genética , Sequência de Bases , Borrelia/classificação , Borrelia/imunologia , Encefalopatias/imunologia , DNA Bacteriano , Feminino , Genoma Bacteriano , Hospedeiro Imunocomprometido , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Febre Recorrente/imunologia , SorotipagemRESUMO
Mice with severe combined immunodeficiency (scid mice) and infected with the relapsing fever agent Borrelia turicatae develop manifestations that resemble those of disseminated Lyme disease. We have characterized two isogenic serotypes, A and B, which differ in their variable small proteins (Vsps) and disease manifestations. Serotype A but not serotype B was cultured from the brain during early infection, and serotype B caused more severe arthritis, myocarditis, and vestibular dysfunction than serotype A. Here we compared the localization and number of spirochetes and the severity of inflammation in scid mice, using immunostained and hematoxylin-and-eosin-stained coronal sections of decalcified heads. Spirochetes in the brain localized predominantly to the leptomeninges, and those in peripheral tissues localized mainly to the extracellular matrix. There were significantly more serotype A than B spirochetes in the leptomeninges and more serotype B than A spirochetes in the skin. The first tissue where spirochetes were observed outside the vasculature was the dura mater. Inflammation was more severe in the skin than in the brain. VspA, VspB, and the periplasmic flagellin protein were expressed in all tissues examined. These findings indicate that isogenic but antigenically distinct Borrelia serotypes can have marked differences in their localization in tissues.